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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastomas, the most frequent and malignant human brain tumors, may develop de novo (primary glioblastoma) or by progression from low-grade or anapalsic astrocytoma (secondary glioblastoma). The molecular alteration most frequent in these tumor-like types is the loss of heterozygosity on chromosome 10, in which several genes have been identified as tumors suppressor. The TP53/MDM2/P14arf and CDK4/RB1/ P16ink4 genetic pathways involved in cycle control are deregulated in the majority of gliomas as well as genes that promote the cellular division, EGFR. Finally the increase of growth and angiogenics factors is also involved in the development of glioblastomas. One of the objectives of molecular biology in tumors of glial ancestry is to try to find the genetic alterations that allow to approach better the classification of glioblastomas, its evolution prediction and treatment. The new pathmolecular classification of gliomas should improve the old one, especially being concerned about the oncogenesis and heterogeneity of these tumors. It is desirable that this classification had clinical applicability and integrates new molecular findings with some known histological features with pronostic value. In this paper we review the most frequent molecular mechanisms involved in the patogenesis of glioblastomas.
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PMID:[Biology molecular of glioblastomas]. 1800 11

There is no standard of care for elderly patients with glioblastoma (GBM) and poor performance status. A 79-year-old woman with GBM, aphasia, and hemiplegia achieved a complete response after only one cycle of temozolomide (TMZ) (150mg/m2/day over 5 days). Genomic profiling of the tumor demonstrated loss of chromosome 10 and MDM2 amplification, which are predictive of poor outcome. The MGMT promoter was methylated, and it is likely that this at least partially explains the exquisite chemosensitivity in our patient. This unusual case report suggests that TMZ warrants further investigation in elderly patients with poor performance status.
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PMID:Complete response after one cycle of temozolomide in an elderly patient with glioblastoma and poor performance status. 1831 94

To further understand the biological significance of amplifications for glioma development and recurrencies, we characterized amplicon frequency and size in low-grade glioma and amplicon stability in vivo in recurring glioblastoma. We developed a 12q13-21 amplicon-specific genomic microarray and a bioinformatics amplification prediction tool to analyze amplicon frequency, size, and maintenance in 40 glioma samples including 16 glioblastoma, 10 anaplastic astrocytoma, 7 astrocytoma WHO grade 2, and 7 pilocytic astrocytoma. Whereas previous studies reported two amplified subregions, we found a more complex situation with many amplified subregions. Analyzing 40 glioma, we found that all analyzed glioblastoma and the majority of pilocytic astrocytoma, grade 2 astrocytoma, and anaplastic astrocytoma showed at least one amplified subregion, indicating a much higher amplification frequency than previously suggested. Amplifications in low-grade glioma were smaller in size and displayed clearly different distribution patterns than amplifications in glioblastoma. One glioblastoma and its recurrencies revealed an amplified subregion of 5 Mb that was stable for 6 years. Expression analysis of the amplified region revealed 10 overexpressed genes (i.e., KUB3, CTDSP2, CDK4, OS-9, DCTN2, RAB3IP, FRS2, GAS41, MDM2, and RAP1B) that were consistently overexpressed in all cases that carried this amplification. Our data indicate that amplifications on 12q13-21 (a) are more frequent than previously thought and present in low-grade tumors and (b) are maintained as extended regions over long periods of time.
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PMID:A different view on DNA amplifications indicates frequent, highly complex, and stable amplicons on 12q13-21 in glioma. 1840 36

MDM2 SNP309 is associated with younger age of tumor onset in patients with Li-Fraumeni syndrome, and TP53 codon 72 polymorphism decreases its apoptotic potential. Glioblastomas frequently show genetic alterations in the TP53 pathway. In the present study, we assessed MDM2 SNP309 in 360 glioblastomas, and correlated these with patient age and survival, as well as other alterations in the TP53 pathway. Frequencies of the MDM2 SNP309 T/T, T/G and G/G genotypes in glioblastomas were 40%, 46% and 14%, respectively. Multivariate analysis showed that MDM2 SNP309 G/G allele was significantly associated with favorable outcome in female glioblastoma patients (hazard ratio 0.54; 95% CI = 0.32-0.92). There was a significant association between MDM2 SNP309 G alleles and TP53 codon 72 Pro/Pro in glioblastomas. Glioblastoma patients with TP53 codon 72 Pro/Pro genotype were significantly younger than Arg/Arg carriers (mean 50.2 vs. 56.1 years; P = 0.018). Multivariate analysis showed that those with TP53 codon 72 Arg/Pro allele had significantly shorter survival than those with Arg/Arg allele (hazard ratio 1.35; 95% CI = 1.07-1.71). Detailed analyses revealed that TP53 codon 72 Pro allele was significantly associated with shorter survival among patients with glioblastomas carrying a TP53 mutation, and among those treated with surgery plus radiotherapy.
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PMID:Common polymorphisms in the MDM2 and TP53 genes and the relationship between TP53 mutations and patient outcomes in glioblastomas. 1846 72

We report on three adult patients with primary glioblastomas showing prominent adipocytic (lipomatous) differentiation, hence referred to as "glioblastomas with adipocyte-like tumor cell differentiation." Histologically, the tumors demonstrated typical features of glioblastoma but additionally contained areas consisting of glial fibrillary acidic protein (GFAP)-positive astrocytic tumor cells resembling adipocytes, that is, containing large intracellular lipid vacuoles. Comparative genomic hybridization (CGH) and focused molecular genetic analyses demonstrated gains of chromosomes 7, losses of chromosomes 9 and 10, as well as homozygous deletion of p14(ARF) in one of the tumors. The second tumor showed gains of chromosomes 3, 4, 8q and 12 as well as losses of chromosomes 10, 13, 15q, 19 and 22. In addition, this tumor carried homozygous deletions of CDKN2A and p14(ARF) as well as point mutations in the TP53 and PTEN genes. The third tumor also had a mutation in the PTEN gene. None of the tumors demonstrated EGFR, CDK4 or MDM2 amplification. Taken together, our results define a rare glioblastoma differentiation pattern and indicate that glioblastomas with adipocyte-like tumor cell differentiation share common molecular genetic features with other primary glioblastomas.
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PMID:Glioblastoma with adipocyte-like tumor cell differentiation--histological and molecular features of a rare differentiation pattern. 1869 Dec 68

The MDM2 gene is amplified and/or overexpressed in about 10% of glioblastomas and constitutes one of a number of ways the p53 pathway is disrupted in these tumours. MDM2 encodes a nuclear phosphoprotein that regulates several cell proteins by binding and/or ubiquitinating them, with p53 being a well-established partner. MDM2 has two promoters, P1 and P2 that give rise to transcripts with distinct 5' untranslated regions. Transcription from P2 is believed to be controlled by p53 and a single-nucleotide polymorphism (SNP309, T>G) in P2 is reported to be associated with increased risk for, and early development of, malignancies. The use of P1 and P2 has not been investigated in gliomas. We used RT-PCR to study P1- and P2-MDM2 transcript expression in astrocytic tumours, xenografts and cell lines with known MDM2, TP53 and p14(ARF) gene status. Both promoters were used in all genetic backgrounds including the use of the P2 promoter in TP53 null cells, indicating a p53-independent induction of transcription. Transcripts from the P1 promoter formed a greater proportion of the total MDM2 transcripts in tumours with MDM2 amplification, despite these tumours having two wild-type TP53 alleles. Examination of SNP309 in glioblastoma patients showed a borderline association with survival but no apparent correlation with age at diagnosis nor with TP53 and p14(ARF) status of their tumours. Our findings also indicate that elevated MDM2 mRNA levels in tumours with MDM2 amplification are preferentially driven by the P1 promoter and that the P2 promoter is not only regulated by p53 but also by other transcription factor(s).
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PMID:p53-independent mechanisms regulate the P2-MDM2 promoter in adult astrocytic tumours. 1878 Nov 78

Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.
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PMID:Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array. 1930 58

Glioblastoma Multiforme (GBM) is a malignant brain cancer that develops after accumulating genomic DNA damage that often includes gene amplifications and/or deletions. These copy number changes can be a critical step in brain tumor development. To evaluate glioblastoma genomic copy number changes, we determined the genome-wide copy number alterations in 31 GBMs. Illumina Bead Arrays were used to assay 22 GBMs and Digital Karyotyping was used on 8 GBM cell lines and one primary sample. The common amplifications we observed for all 31 samples was GLI/CDK4 (22.6%), MDM2 (12.9%) and PIK3C2B/MDM4 (12.9%). In the 22 GBM tumors, EGFR was amplified in 22.7% of surgical biopsies. The most common homozygously deleted region contained CDKN2A/CDKN2B (p15 and p16) occurring in 29% of cases. This data was compiled and compared to published array CGH studies of 456 cases of GBMs. Pooling our Illumina data with published studies yielded these average amplification rates: EGFR-35.7%, GLI/CDK4-13.4%, MDM2-9.2%, PIK3C2B/MDM4-7.7%, and PDGFRA-7.7%. The CDKN2A/CDKN2B locus was deleted in 46.4% of the combined cases. This study provides a larger assessment of amplifications and deletions in glioblastoma patient populations and shows that several different copy number technologies can produce similar results. The main pathways known to be involved in GBM tumor formation such as p53 control, growth signaling, and cell cycle control are all represented by amplifications or deletions of critical pathway genes. This information is potentially important for formulating targeted therapy in glioblastoma and for planning genomic studies.
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PMID:A survey of glioblastoma genomic amplifications and deletions. 1960 42

There is limited knowledge on the in vivo behavior of amplified regions in human tumors. First evidence indicates that amplicon structures are largely maintained in recurrent tumors. Here, we investigated the fate of amplified regions in several independent cases of recurrent glioblastoma and the possible association of 12q13-21 amplifications and survival. We analyzed 12q13-21 amplicon numbers and sizes in glioblastoma and their recurrences by array-CGH. The majority of the 12q13-21 amplicons found in the original tumor are lost in the subsequent recurrence. Likewise, the majority of the amplicons found in the first recurrence are lost in the second recurrence. The remaining amplicons of recurrences often expanded or were maintained in size. Because of re-emergences and de novo appearances of amplicons, however, the overall number of amplicons did not decrease in the recurrences. Understanding genetic changes including gene amplifications in the development of tumor recurrences will contribute to rational therapeutic strategies for an improved patient survival. We recognized a significant longer survival time in glioblastoma patients that lack amplifications of either CDK4, CYP27B1, XRCC6BP1 (KUB3), or MDM2.
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PMID:Amplicons on chromosome 12q13-21 in glioblastoma recurrences. 1983 52

Glioblastomas express a notable heterogeneity in both the histological and cell patterns with glial astrocytic differentiation. Primary glioblastoma, which is the most frequent presentation (90-95%), occurs mainly in older patients and arises de novo, without any clinical or histological evidence of a less malignant precursor lesion. EGFR amplification has been identified as a genetic hallmark of primary glioblastomas and occurs in 40-60% of cases. However, there exist primary glioblastomas without EGFR amplification/overexpression. The purpose of this study was to stabilize the association between cases with and without EGFR gene amplification with clinical and genetic parameters in 45 cases of primary glioblastomas. EGFR amplification was observed in 24 cases (53%), while in the remaining 21 cases (47%) this alteration was not displayed. And whereas EGFR was overexpressed in 79% of cases with EGFR amplification, only 33% of the cases without EGFR amplification showed overexpression. The amplification of EGFR was associated with amplifications in MDM2 and CDK4 and a higher percentage of cases with promoter methylation of INK4a. Only one case of glioblastoma with EGFR amplification presented TP53 mutation simultaneously. Seven remaining cases with TP53 mutations were glioblastomas without EGFR amplification. The INK4a, INK4b and ARF deletions were similar in the two groups. Primary glioblastomas with and without EGFR amplification did not show any significant differences in average survival. The genetic studies suggest the existence of molecular subtypes within primary glioblastoma that may, when fully defined, contribute toward the development of drugs that specifically target tumors with divergent genetic profiles.
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PMID:Primary glioblastomas with and without EGFR amplification: relationship to genetic alterations and clinicopathological features. 2005 Oct 17


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